N-(aryl/heteroaryl) amino acid derivatives pharmaceutical compositions comprising same and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds

Abstract

Disclosed are compounds which inhibit β-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits β-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.

What is claimed is: 
     
       1. A method for inhibiting β-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds effective in inhibiting the cellular release and/or synthesis of β-amyloid peptide wherein said compounds are represented by formula I: ##STR9## wherein: R 1  is selected from the group consisting of (a) phenyl,   (b) a substituted phenyl group of formula II: ##STR10##  wherein R c  is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein R b  and R c  are fused to form a heteroaryl or heterocyclic ring with the phenyl ring,   R b  and R b'  are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when R c  is hydrogen, then R b  and R b'  are either both hydrogen or both substituents other than hydrogen, (c) 2-naphthyl,   (d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl,   (e) heteroaryl, and   (f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the --NH group;     R 2  is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl provided that the substituents are not ortho to the attachment of the aryl or heteroaryl atom to the carbon atom;   R 3  is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, and heterocyclic;   X is --C(O)Y where Y is selected from the group consisting of (a) alkyl,   (b) substituted alkyl with the proviso that the substitution on said substituted alkyl does not include α-haloalkyl, α-diazoalkyl or α-OC(O)alkyl groups,   (c) alkoxy or thioalkoxy,   (d) substituted alkoxy or substituted thioalkoxy,   (e) hydroxy,   (f) aryl,   (g) heteroaryl,   (h) heterocyclic,   (i) --NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and     when R 3  contains at least 3 carbon atoms, X can also be --CR 4  R 4  Y' where each R 4  is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, --OC(O)R 5 , --SSR 5 , --SSC(O)R 5  where R 5  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,   and with the proviso that when R 1  is 3,4-dichlorophenyl, R 2  is methyl, and R 3  is benzyl derived from D-phenylalanine, then X is not --C(O)OCH 3 .   
     
     
       2. A method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I: ##STR11## wherein: R 1  is selected from the group consisting of (a) phenyl,   (b) a substituted phenyl group of formula II: ##STR12##  wherein R c  is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein R b  and R c  are fused to form a heteroaryl or heterocyclic ring with the phenyl ring,   R b  and R b'  are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when R c  is hydrogen, then R b  and R b'  are either both hydrogen or both substituents other than hydrogen, (c) 2-naphthyl,   (d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl,   (e) heteroaryl, and   (f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the --NH group;     R 2  is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl provided that the substituents are not ortho to the attachment of the aryl or heteroaryl atom to the carbon atom;   R 3  is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, and heterocyclic;   X is --C(O)Y where Y is selected from the group consisting of (a) alkyl,   (b) substituted alkyl with the proviso that the substitution on said substituted alkyl does not include α-haloalkyl, α-diazoalkyl or α-OC(O)alkyl groups,   (c) alkoxy or thioalkoxy,   (d) substituted alkoxy or substituted thioalkoxy,   (e) hydroxy,   (f) aryl,   (g) heteroaryl,   (h) heterocyclic,   (i) --NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and     when R 3  contains at least 3 carbon atoms, X can also be --CR 4  R 4  Y' where each R 4  is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, --OC(O)R 5 , --SSR 5 , --SSC(O)R 5  where R 5  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,   and with the proviso that when R 1  is 3,4-dichlorophenyl, R 2  is methyl, and R 3  is benzyl derived from D-phenylalanine, then X is not --C(O)OCH 3 .   
     
     
       3. A method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I: ##STR13## wherein: R 1  is selected from the group consisting of (a) phenyl,   (b) a substituted phenyl group of formula II: ##STR14##  wherein R 1  is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein R b  and R c  are fused to form a heteroaryl or heterocyclic ring with the phenyl ring,   R b  and R b'  are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when R c  is hydrogen, then R b  and R b'  are either both hydrogen or both substituents other than hydrogen, (c) 2-naphthyl,   (d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl,   (e) heteroaryl, and   (f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the --NH group;     R 2  is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl provided that the substituents are not ortho to the attachment of the aryl or heteroaryl atom to the carbon atom;   R 3  is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, and heterocyclic;   X is --C(O)Y where Y is selected from the group consisting of (a) alkyl,   (b) substituted alkyl with the proviso that the substitution on said substituted alkyl does not include α-haloalkyl, α-diazoalkyl or α-OC(O)alkyl groups,   (c) alkoxy or thioalkoxy,   (d) substituted alkoxy or substituted thioalkoxy,   (e) hydroxy,   (f) aryl,   (g) heteroaryl,   (h) heterocyclic,   (i) -NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and     when R 3  contains at least 3 carbon atoms, X can also be --CR 4  R 4  Y' where each R 4  is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, --C(O)R 5 , --SSR 5 , --SSC(O)R 5  where R 5  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,   and with the proviso that when R 1  is 3,4-dichlorophenyl, R 2  is methyl, and R 3  is benzyl derived from D-phenylalanine, then X is not --C(O)OCH 3 .   
     
     
       4. The method according to claim 1, 2 or 3 wherein R 1  is phenyl, 2-naphthyl, quinolin-3-yl, benzothiazol-6-yl, and 5-indolyl. 
     
     
       5. The method according to claim 1, 2 or 3 wherein R 1  is a substituted phenyl group of the formula: ##STR15## wherein R c  is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein R b  and R c  are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, R b  and R b'  are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when R c  is hydrogen, then R b  and R b'  are either both hydrogen or both substituents other than hydrogen.   
     
     
       6. The method according to claim 1, 2 or 3 wherein R 1  is a substituted 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl. 
     
     
       7. The method according to claim 1, 2 or 3 wherein R 1  is a substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the --NH group. 
     
     
       8. The method according to claim 5 wherein R 1  is a 4-substituted, a 3,5-disubstituted or 3,4-disubstituted phenyl. 
     
     
       9. The method according to claim 8 wherein R 1  is a 3,5-disubstituted phenyl. 
     
     
       10. The method according to claim 9 wherein the 3,5-disubstituted phenyl is selected from the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)phenyl and 3,5-dimethoxyphenyl. 
     
     
       11. The method according to claim 8 wherein R 1  is a 3,4-disubstituted phenyl. 
     
     
       12. The method according to claim 11 wherein the 3,4-disubstituted phenyl is selected from the group consisting of 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl and 3,4-methylenedioxyphenyl. 
     
     
       13. The method according to claim 8 wherein R 1  is a 4-substituted phenyl. 
     
     
       14. The method according to claim 13 wherein the 4-substituted phenyl is selected from the group consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl; 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl, and 4-(1-ethoxy)ethylphenyl. 
     
     
       15. The method of claims 1, 2 or 3 wherein R 1  is 2-methylquinolin-6-yl. 
     
     
       16. The method according to claims 1, 2 or 3 wherein R 2  is selected from the group consisting of alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms and aryl. 
     
     
       17. The method according to claim 16 wherein R 2  is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, so-butyl, --CH 2  CH 2  SCH 3  and phenyl. 
     
     
       18. The method according to claims 1, 2 or 3 wherein R 3  is an alkyl group. 
     
     
       19. The method according to claim 18 wherein the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and sec-butyl. 
     
     
       20. The method according to claims 1, 2 or 3 wherein R 3  is a substituted alkyl group. 
     
     
       21. The method according to claim 20 wherein the substituted alkyl group is selected from the group consisting of α-hydroxyethyl, --CH 2  -cyclohexyl, benzyl, p-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3,5-diiodo-4-hydroxybenzyl, --CH 2  -indol-3-yl, --(CH 2 ) 4  --NH-BOC, --(CH 2 ) 4  --NH 2 , --CH 2  -(1-N-benzyl-imidazol-4-yl), --CH 2  -imidazol-4-yl, --CH 2  CH 2  SCH 3 , --(CH 2 ) 4  NHC(O)(CH 2 ) 3  CH 3 , and --(CH 2 ) y  C(O)OR 5  where y is 1 or 2 and R 5  is hydrogen, methyl, or tert-butyl. 
     
     
       22. The method according to claims 1, 2 or 3 wherein X is --C(O)Y wherein Y is selected from the group consisting of alkoxy and thioalkoxy. 
     
     
       23. The method according to claim 22 wherein Y is alkoxy selected from the group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, and tert-butoxy. 
     
     
       24. The method according to claims 1, 2, or 3 wherein X is --C(O)Y and Y is --NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups. 
     
     
       25. The method according to claim 24 wherein Y is selected from the group consisting of amino (--NH 2 ), N-(iso-butyl)amino, N-methylamino, N,N-dimethylamino, and N-benzylamino. 
     
     
       26. The method according to claims 1, 2 or 3 wherein X is --CH 2  OH. 
     
     
       27. The method according to claims 1, 2 or 3 wherein the compound of formula I is selected from the group consisting of: N-[N-(3,4-dichlorophenyl)alanyl]valine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]valine N-iso-butyl amide   N-[N-(3,4-dichlorophenyl)alanyl]threonine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]valine ethyl ester   N-[N-(3,4-dichlorophenyl)alanyl]valine tert-butyl ester   N-[N-(3,4-dichlorophenyl)alanyl]valine amide   N-(3,4-dichlorophenyl)alanine N-(1-hydroxy-3-methyl-2-butyl)amide   N-[N-(3,4-dichlorophenyl)alanyl]valine N,N-dimethyl amide   N-[N-(3,4-dichlorophenyl)alanyl]valine N-methyl amide   N-[N-(3,4-dichlorophenyl)alanyl]alanine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]leucine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]phenylalanine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]isoleucine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]-2-aminopentanoic acid methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanoic acid methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]tryptophan methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid α-methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid β-(tert-butyl ester)α-methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]-N-BOC-lysine methyl ester   N-[N-benzothiazol-6-yl)alanyl]-2-aminohexanoic acid methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]lysine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]tyrosine methyl ester   N-[N-(3,5-dichlorophenyl)alanyl]alanine methyl ester   N-[N-(3,5-dichlorophenyl)alanyl]-2-aminopentanoic acid methyl ester   N-[N-(3,5-dichlorophenyl)alanyl]phenylalanine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid β-(methyl ester)α-methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]-1-benzylhistidine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]glutamic acid γ-(tert-butyl ester)α-methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]leucine amide   N-[N-(3,4-dichlorophenyl)alanyl]glutamic acid α-methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]-(3,5-diiodo)tyrosine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]-(3-iodo)tyrosine methyl ester   N-[N-(3,5-dichlorophenyl)glycyl]-2-aminopentanoic acid methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]-Nε-(hexanoyl)lysine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]phenylalanine amide   N-[N-(3,4-dichlorophenyl)alanyl-]2-aminohexan-(N-methyl)-amide   N-[N-(3,4-dichlorophenyl)alanyl-]β-cyclohexylalanine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanamide   N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexan-(N,N-dimethyl)-amide   N-[N-(3,4-dichlorophenyl)alanyl]methionine methyl ester   N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexan-(N,N-dimethyl)-amide   N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexanamide   N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexan-(N-methyl)-amide   N-[N-(3,4-dichlorophenyl)alanyl]histidine methyl ester   N-[N-(quinolin-3-yl)alanyl]-2-aminohexanoic acid methyl ester   N-[N-(benzothiazol-2-yl)-L-alanyl]-2-aminohexanoic acid methyl ester   N-[N-(3,5-difluorophenyl)alanyl]alanine methyl ester   N-[N-(3,5-difluorophenyl)alanyl]-2-aminohexanoic acid methyl ester   N-[N-(3,4-dichlorophenyl)-L-alanyl]-S-2-aminohexanamide   N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexan-(N-benzyl)-amide   N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-2-amino-2-phenylethanol   N-[N-(3,5-dichlorophenyl)phenylglycinyl]alanine methyl ester   N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanol   N-[N-(3,5-dichlorophenyl)alanyl]-2-amino-2-phenylethanol   N-[N-(3,5-dichlorophenyl)-L-alanyl]-L-phenylglycine tert-butyl ester   N-[N-(3,5-di-(trifluoromethyl)phenyl)-L-alanyl]-L-phenylglycine tert-butyl ester   N-[N-(3,5-dimethoxyphenyl)-L-alanyl]-2-aminohexanoic acid methyl ester and pharmaceutically acceptable salts thereof.